Lincomycin analogs

ABSTRACT

LOCATED IN THE 7(S)-position when R1 and R2 are taken independently, A represents hydrogen or hydroxyl, B represents hydrogen or hydroxyalkyl, n is the integer 0 when B is hydroxyalkyl and n is an integer of 0 to 1, inclusive, when B is hydrogen, X is oxygen or sulfur, D is the acyl radical of a lower hydrocarbon carboxylic acid; R4 is lower alkyl and Y is carboxacyl or hydrogen. Disclosed also are methods of making and using the novel compounds of the invention, which are useful intermediates in the chemical synthesis of useful antibacterial lincomycin analogs. Certain of the compounds of the invention are also active as antibacterial agents.   WHEREIN Z and R5 are as defined above; R3 is hydrogen when R1 and R2 are taken together and is a monovalent thio group of formula:   WHEREIN Z is hydrogen, lower alkyl or a protective group removable by hydrogenolysis; R5 is lower alkyl; R1 and R2 when together are the divalent group;   WHEREIN Ac is carboxacyl or an acyl group of formula:   ARE DISCLOSED, WHEREIN R1 taken independently is hydrogen; R2 taken independently is the moiety   Compounds of the formula:

United States Patent [191 Bannister 1 Mar. 11, 1975 1 1 LINCOMYCINANALOGS [75] Inventor: Brian Bannister, Kalamazoo, Mich.

[731 Assignec: The Upjohn Company, Kalamazoo,

Mich.

122] Filed: Mar. 6, 1973 I21] Appl. No.: 338,459

Primary Examiner-Johnnie R. Brown Attorney, Agent, or Firm-Joseph T.Eisele; Roman Saliwanchik [57] ABSTRACT Compounds of the formula:

are disclosed, wherein R taken independently is hydrogen; R takenindependently is the moiety wherein Ac is carboxacyl or an acyl group offormula:

wherein Z is hydrogen. lower alkyl or a protective group removable byhydrogenolysis; R is lower alkyl; R and R when together are the divalentgroup;

N QM R It wherein Z and R are as defined above; R; is hydrogen when R,and R are taken together and is u monovw lent thio group of formula:

located in the 7(S)-position when R and R are taken independently, Arepresents hydrogen or hydroxyl. B represents hydrogen or hydroxyalkyl,n is the integer 1) when B is hydroxyalkyl and n is an integer of 0to 1. inclusive, when B is hydrogen, X is oxygen or sulfur. D is theacyl radical of a lower hydrocarbon carboxylic acid; R is lower alkyland Y is carboxacyl or hydrogen.

Disclosed also are methods of making and using the novel compounds ofthe invention, which are useful intermediates in the chemical synthesisof useful antibacterial lincomycin analogs. Certain of the compounds ofthe invention are also active as antibacterial agents.

21 Claims, N0 Drawings LINCOMYCIN ANALOGS BACKGROUND OF THE INVENTION 1.Field of the Invention The invention concerns a-thiolincosaminidederivatives; their preparation and uses as intermediates in the chemicalsynthesis of lincomycin analogs. More particularly, the inventionconcerns novel alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy-ot-thiolincosaminides and novel alkyl7-deoxy-7(S)-acyloxythioalkyl-athiolincosaminides, their preparation anduse.

2. Description of the Prior Art7-0-Alkyl-substituted'a-thiolincosaminides and their preparation fromalkyl N-acyl-6,7-aziridino-athiolincosaminides are described in U.S.Pat. No. 3,702,322.

Iranian Pat. No. 10,460 of Aug. 15, 1972 (copending U.S. applicationSer. No. 237,129; filed Mar. 22, 1972, now Pat. No. 3,790,560) describesalkyl 7-deoxy-7- mercaptoalkylthio-a-thiolincosaminides, theirpreparation by sulfidolysis of appropriate 6,7-aziridino-6-deamino-7-deoxy-a-thiolincosaminides and their conversion tocorresponding lincomycin analogs.

Iranian Pat. No. 10,395 of Aug. 15, 1972 (copending U.S. applicationSer. No. 198,990; filed Nov. 15, 1971, now abandoned) discloses alkyl7-deoxy-athiolincosaminides having a variety of substituted thio groupsin the 7(S)-position, such as for example, alkylthio, hydroxyalkylthioand acetoxyalkylthio groups. Also disclosed are preparative proceduresfor such compounds, which comprises sulfidolysis of appropriate6,7-aziridino-6-deamino-7-deoxy-athiolincosaminides and use of theproduct compounds to prepare lincomycin analogs.

Iranian Pat. No. 10,407 of Aug. 15, 1972 (copending U.S. applicationSer. No. 199,046; filed Nov. 15, 1971, now U.S. Pat. No. 3,767,649)discloses in particular the compound methylN-acetyl-2,3,4-tri--acetyl-7(S)-I3-(3-acetoxypropylthio)propylthio]-7-deoxy-athiolincosaminide andlincomycin analogs thereof. The patent teaches preparation of theparticular compound by addition of trimethylene sulfide to methylN-acetyl-2,3,4-tri-0-acetyl-6,7-aziridino-6-deamino-7-deoxy-athiolincosaminide.

In general, the compounds of the present invention are intermediates forpreparing many of the compounds disclosed in the above described Iranianpatents. None of the intermediate compounds of my present invention canbe prepared by the process set forth in the above described patents.

The process of the invention comprises, broadly, the sulfidolysis ofcertain alkyl 6,7-aziridino-6-deamino-7- deoxy-a-thiolincosaminideemploying a particular class of cyclic sulfur compounds. The products ofthe process are obtained in very high yields, about twice the yields ofsulfidolated products obtained in those processes of Iranian Pat. Nos.10,395; 10,407 and 10,460,

supra.

Since the 7(S)-S-substituted compounds obtained by the process of thisinvention are quantitatively converted upon hydrolysis to certain ofthose sulfidolated products of said Iranian Patents, the process of thepresent invention and the products thereof offer a commerciallyadvantageous means of preparing 7(8)- thiosubstituted lincomycins.

Moreover, the process of the invention provides a method of obtainingintermediate compounds useful for preparing a class of antibacterialagents not previously known, or preparable by previously known methods;i.e., the alkyl N-(L-2-pyrrolidincarboxyacyl)-7-deoxy-7(S)-(acetoxymethoxy)-alkylthio-athiolincosaminides, and the alkylpyrrolidinecarboxacyl)-7-deoxy-7(S)acetoxymethylthio)-alkylthio-a-thiolincosaminides.

Alkyl N-carboxacyl-6,7-aziridino-6deamino-7- deoxy-oz-thiolincosaminideshave also been disclosed prior hereto; see for example, U.S. Pat. Nos.3,671,647 and 3,702,332; Iranian Pat. Nos. 10,395 and 10,460. However,attempts to obtain the alkyl N-(L-2-pyrrolidinecarboxacyl)-6,7-aziridino-6-deamino-7-deoxy-a-thiolincosaminides of the invention by methods taught in theabove references for preparing the N- carboxacyl analogs, i.e., byN-acylation of the aziridino with an L-2-pyrrolidine-carboxylic acid orthe corresponding l-alkyl substituted L-2-pyrrolidinecarboxylic acidhave met with failure prior hereto. By the novel process disclosedherein, alkyl N-(l-carbobenzoxy-4'alkyl)-6,7-aziridino-6-deamino-7-deoxy-athiolincosaminides are prepared,from which the corresponding useful 1'hydrogen and 1'-alkyl analogs areobtained.

SUMMARY OF THE INVENTION 30 The invention comprises compounds of theformula:

wherein R when taken independently represents hydrogen; R when takenindependently represents the monovalent moiety t Ac- N- wherein Ac isselected from carboxacyl and an acyl radical of formula:

Z l N wherein Z is selected from hydrogen, lower alkyl and a protectivegroup removable by hydrogenolysis; R is lower alkyl; R, and R when takentogether form the divalent moiety of formula:

Z l N wherein Z and R are as defined above: R is hydrogen when R and Rare taken together and when R, and R are taken independently, R is amonovalent thio group in the 7(S)-position having the formula:

wherein A is selected from hydrogen and hydroxyl, B is selected fromhydrogen and hydroxyalkyl, n is the integer when E is hydroxyalkyl and nis an integer of from O to l, inclusive, when B is hydrogen, X isselected from oxygen and sulfur, D is an acyl radical of a lowerhydrocarbon carboxylic acid; R represents lower alkyl; and Y is selectedfrom carboxacyl and hydrogen.

The wavy line joining R to the body of the molecule as shown in formula(I) indicates that the group R may be in either the cis (below the planeof the nitrogencontaining ring) or trans (above the plane of thenitrogen-containing ring).

The wavy line joining the methyl group and R to the carbon atom atposition number 7 in the formula (I) indicates that certain of thecompounds (I) exist in both 6(R), 7(R) and 6(R), 7(S) epimeric forms,i.e., those compounds (I) wherein R, and R are taken together have thestructure:

Z CH

6(R), 7(R) form The term carboxacyl as used throughout the specificationand claims means the acyl radical of a hydrocarbon carboxylic acid or ofa hydrocarbon carboxylic 0 II E- 0- wherein E is hydrocarbyl of from 1to about 17 carbon atoms, inclusive, or hydrocarbyl of from 1 to about17 carbon atoms, inclusive, wherein a hydrogen atom has been replacedwith an inert substituent group. Illustrative of acyl radicals of ahydrocarbon carboxylic acid wherein E is hydrocarbyl are the acylradicals of (a) saturated or unsaturated, straight or branched chainaliphatic carboxylic acids, for example, acetic, propionic, butyric,isobutyric, tert-butylacetic, valeric, isovaleric, caproic caprylic,decanoic, dodecanoic, lauric, tridecanoic, myristic, pentadecanoic,palmitic, margaric stearic, acrylic, crotonic, undecylenic, oleic,hexynoic, heptynoic, octynoic acids and the like; (b) saturated orunsaturated, alicyclic carboxylic acids, for example,cyclobutanecarboxylic acid, cyclopentanecarboxylic acid,cyclopentenecarboxylic acid, methylcyclopentenecarboxylic acid,cyclohexanecarboxylic acid, dimethylcyclohexenecarboxylic acid,dipropylcyclohexanecarboxylic acid, and the like; (c) saturated orunsaturated, alicyclic aliphatic carboxylic acids, for example,cyclopentaneacetic acid, cyclopentanepropionic acid, cyclohexanebutyricacid, methylcyclohexaneacetic acid, and the like; (d) aromaticcarboxylic acids, for example, benzoic acid, toluic acid, naphthoicacid, ethylbenzoic acid, isobutylbenzoic acid, methylbutylbenzoic acid,and the like; and (e) aromaticaliphatic carboxylic acids, for example,phenylacetic acid, phenylpropionic acid, phenylvaleric acid, cinnamicacid, phenylpropionic acid, and naphthylacetic acid, and the like.

The term hydrocarbon carboxylic acid substituted with an inert group isused herein to mean a hydrocarbon carboxylic acid wherein one or morehydrogen atoms attached directly to a carbon atom have been replacedwith a group inert to reaction under the conditions hereinafterdescribed for preparing compounds (I) of the invention. Illustrative ofsuch substituent groups are halo-, nitro-, hydroxy-, amino-, cyanothiocyano-, or alkoxy-groups. Illustrative of halo-, nitro-, hydroxy-,amino-, cyano-, thiocyanoand alkoxysubstituted hydrocarbon carboxylicacids re mono-, di-,

and trichloroacetic acid; aand B- chloropropionic acid; aand'y-bromobutyric acid; aand 8 iodovaleric acid; mevalonic acid; 2- and4-chlorocyclohexanecarboxylic acid; shikimic acid; 2-nitro- 1-methylcyclobutanecarboxylic acid; 1,2,3 ,-4,5 ,6-hexachlorocyclohexanecarboxylic acid; 3-bromo-2-methylcyclohexanecarboxylic acid; 4- and S-bromo-Z-methylcyclohexanecarboxylic acid; 5- and 6-bromo-2-methylcyclohexanecarboxylic acid; 2,3-dibromo-2-methylcyclohexanecarboxylic acid; 2,5-dibromo-2-methylcyclohexanecarboxylic acid; 4,5-dibromo-2-methylcyclohexanecarboxylic acid; 5 ,6-dibromo-2-methylcyclohexanecarboxylic acid; 3-bromo-3- methylcyclohexanecarboxylicacid; 6-bromo-3- methylcyclohexanecarboxylic acid; 1,6-dibromo-3-methylcyclohexanecarboxylic acid; 2-bromo 4- methylcyclohexanecarboxylicacid; l,2-dibromo-4- methylcyclohexanecarboxylic acid; 3-bromo-2,2,3-

trimethylcyclopentanecarboxylic acid; l-bromo-3,5-dimethylcyclohexanecarboxylic acid; homogentisic acid; 0-, m-, andp-chlorobenzoic acid; anisic acid; salicylic acid; p-hydroxybenzoicacid; B-resorcylic acid; gallic acid; veratric acid; trimethoxybenzoicacid; trimethoxycinnamic acid; 4,4-dichl0robenzilic acid; 0-, m-, andp-nitrobenzoic acid; cyanoacetic acid; 3,4- and 3,5dinitrobenzoic acids;2,4,6-trinitrobenzoic acid; thiocyanoacetic acid; cyanopropionic acid;lactic acid; ethoxyformic acid (ethyl hydrogen carbonate);butyloxyformic acid; pentyloxyformic acid; hexyloxyformic acid;dodecyloxyformic acid; hexadecyloxyformic acid and the like.

The term protective group removable by hydrogenolysis as used hereinmeans a group inert to acylation but readily removable byhydrogenolysis. Such groups are well known in the art, and areillustrated by trityl, diphenyl-(p-methoxyphenyl)methyl,bis-(p-methoxyphenyl)phenylmethyl, benzyl, or p-nitrobenzyl andhydrocarbyloxycarbonyl groups. Examples of the latter aretertiary-butoxycarbonyl; benzyloxycarbonyl groups of the formula:

I H CH 0- C- wherein W is hydrogen, nitro, methoxy, chloro, or bromo,for example, carbobenzoxy, pnitrocarbobenzoxy, p-bromo-, andpchlorocarbobenzoxy-; and phenyloxycarbonyl groups of the formula:

wherein W, is hydrogen, ally], or alkyl of not more than 4 carbon atoms,such as phenyloxycarbonyl, ptolyloxycarbonyl, p-ethylphenyloxycarbonyl,and p-allylphenyloxycarbonyl and the like.

The term lower alkyl is employed in its usual sense as meaning alkyl offrom I to about 8 carbon atoms, inelusive, such as methyl, ethyl,propyl, butyl, pentyl, hexyl, heptyl, octyl and isomeric forms thereof.

The term R, and R when taken together means R and R together mayconstitute a single group, and when so taken will represent the abovedescribed divalent moiety having its valencies satisfied by covalentbonds to carbon atoms at positions 6 and 7, respectively, in the formula(I). i

The term hydroxyalkyl as used herein means alkyl as defined abovewherein a hydrogen atom has been replaced by a hydroxyl group.Illustrative of hydroxyalkyl are hydroxyalkyl having from I to 6 carbonssuch as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,hydroxypentyl and hydroxyhexyl.

The term acyl radical of a lower hydrocarbon carboxylic acid means anacyl radical of a hydrocarbon carboxylic acid as defined above, havingfrom I to about 8 carbon atoms, inclusive.

One skilled in the art will appreciate that those compounds (I) whereinA or B in the group R are other than hydrogen may exist in both D- and Ldiastereoisomeric forms. It is to be understood that the formula (l)above includes both the D- and L- diastereoisomers.

Compounds (I) of the invention are useful intermediates in the chemicalsynthesis of known lincomycin analogs which are antibacterial agents,The invention also comprises methods of preparing and using thecompounds (I) of the invention. These methods of preparation and usewill be described in greater detail hereinafter.

DETAILED DESCRIPTION OF THE INVENTION The process of the invention iscarried out according to the following procedures.

PROCESS A Those compounds (I) of the invention wherein Z (if present) isspecifically a protective group removable by hydrogenolysis or loweralkyl and R is specifically the above described thio group, i.e., Acompound of the formula:

wherein A, B, X, D, n, R and Y are as previously defined; and Ac iscarboxacyl or an acyl radical of the formula:

G l N wherein R is as defined above and G is a protective groupremovable by hydrogenolysis or lower alkyl; are readily prepared bybringing together the corresponding alkylN-acyl-6,7-aziridino-6-deamino-7-deoxy-athiolincosaminide (III) with asulfur compound of the formula:

wherein A, B, X and n have the meanings previously ascribed to them, andan anhydrous lower hydrocarbon carboxylic acid (V).

The reaction which occurs is conveniently illustrated by the schematicformula:

(l l I) Ha B l H C- S-CH C) C-X-CH O-D l I l H H Ac N C H wherein Ac RA, B, D, X, Y, n and the wavy lines are as defined above.

As illustrated in the above reaction scheme, the starting alkylN-acyl-6,7-aziridino-6-deamino-7-deoxy-athiolincosaminide (Ill) startingcompound, Le, a 6(R), 7(R)-form is converted to the corresponding 7(S)-4O derivative, (i.e., L-threo configuration) as a result of theinversion of the 7(R)-position in the 6(R), 7(R)- form during the courseof the reaction.

The compounds ([1) of the invention are useful intermediate compounds.Upon removal of acyl groups (Ac D or Y wh'en Y is carboxacyl) byhydrazinolysis, for example, by hydrazinolysis following the procedureset forth in US. Pat. No. 3,179,565, there is obtained the correspondingcompound of formula:

wherein A, B, n, X and R are as defined above.

The compounds (V1) may be N-acylated with the mixed anhydride oftrans-propyl-hygric acid and monoisobutyl carbonate (obtained byreacting transpropylhygric acid with isobutyl chloroformate) by themethod disclosed in US. Pat. No. 3,380,992, to obtain the corresponding7(S)-S-substituted lincomycins. The latter compounds are usefulantibacterial agents; see, for example, Iranian Pats. Nos. 10,395 and10,460, su-

p In carrying out the Process A of the invention as illustrated above,reactants (III), (IV) and (V) are brought together and admixed usingconventional apparatus and techniques. The reaction proceedssatisfactorily under a broad range of temperatures conditions, i.e.,within a range of from about 25C. to about 180C. Preferably, the processof the invention is carried out within a temperature range of from aboutC. to about 150C. and most preferably within a temperature range of fromabout C. to about 1 10C. The proportions of reactants (III), (IV) and(V) and not critical to the process reaction, but influence the yieldsof product compounds (II). The proportions employed may bestoichiometric, i.e., substantially equimolar. Optimum yields areobtained by employing the acid reactant (V) in excess; i.e., in aproportion of at least 2 molar equivalents and preferably within a rangeof from about 2 to 8 molar equivalents. The sulfar compound (lV)reactant is advantageously employed in excess of stoichiometricrequirements, i.e., a molar excess and preferably in a proportion of atleast 2 molar equivalents, and most preferably within a range of fromabout 2 molar equivalents to about 60 molar equivalents.

Advantageously, the above described reaction is carried out in thepresence of an inert organic solvent. An inert organic solvent isdefined for the purpose of this invention as an organic solvent whichwill at least partially solubilize the thiolincosaminide reactant (Ill)and which does not enter into or in any way adversely affect the desiredcourse of the reaction. Illustrative of inert organic solvents aredioxane, carbon tetrachloride, chlorform, methylene chloride, benzene,toluene, nhexane and like organic solvents. Preferred as the organicsolvent is an excess of sulfur compound (1V) i.e., in a proportionbeyond that required for the above described reaction, provided saidsulfur compound (IV) meets the above criteria for solubilizing reactant(Ill) at the temperature selected for carrying out the process.

in general, the above described reaction is complete in from aboutone-quarter to about 24 hours, depending upon the nature of the groupsAc A, B, D, X, and Y in the formulae (H) and (ill). Completion of thereaction may be ascertained by conventional analytical procedures suchas, for example, by vapor-phase chromatography, thin-layerchromatography and like procedures which will indicate the disappearanceof starting compounds (Ill) and the appearance of the desired productcompounds (11).

Upon completion of the reaction, the compounds (11) of the invention arereadily separated from the reaction mixture by conventional procedures.For example, excess solvent and excess reactants (1V) and (V) areremoved by distillation to leave a residue of crude compounds (ll).Purified compounds ([1) of the invention are separated from the cruderesidue by well known techniques such as, for example, bycounter-current distribution, chromatograpy and solvent extractiontechniques followed by crystallization.

The acid reactant starting compounds of formula (V) in anhydrous form aswell known compounds. In general they may be characterized by theirhaving an acidity constant of at least about K 1.7 X 10? Illustrative ofanhydrous lower hydrocarbon carboxylic acids (V) are dry lower alkanoicacids having 2 to 8 carbon atoms, inclusive, such as acetic acid,propionic acid and octanoic acid; arenoic acids having 7 to 8 carbonatoms, inclusive, such as benzoic acid and toluic acid. Preferred as theanhydrous hydrocarbon carboxylic acid is glacial acetic acid.

The sulfur compound reactants of formula (IV) are generally well knowncompounds as is their preparation. Those compounds (IV) wherein A and Bare each hydrogen are the well known compounds 1,3- oxathiolane,1,3-dithiolane, 1,3-oxathiane and 1,3- dithiane. The hydroxy-substituteddithiane and the hydroxyalkyl-substituted dithiolanes are readilyprepared following the method of E. J. Corey, et al., Angcwandte Chemie,International Edition (England), 4, 1075, (1965). In general, the methodcomprises reacting an appropriate hydroxyalkanedithiol withdimethoxymethane in the presence of boron fluoride. Thus, for example,employing 1,3-dimercapto-2-propanol as the startinghydroxy-alkanedithiol, there is obtained hydroxy-l ,3-dithiane.

Employing a hydroxyalkanedithiol of formula:

HS SH (VII) wherein P is an integer of 1 to 6; there is obtained a4-hydroxya1kyI-1,3-dithiane within the scope of the formula (IV).Illustrative of such 4-hydroxyalkyl-l,3- dithiolanes are4-hydroxymethyl-l,3-dithiolane, 4-(2- hydroxyethyl)-1,3'dithiolane,4-(1-methyl-lhydroxyethyl)-l ,3-dithiolane, 4-9l,1-dimethyl-2hydroxyethyl)-l,3-dithiolane. 4-(5-hydroxypentyl)- 1,3-dithiolane and4-(6-hydroxyhexyl)-l ,3-dithiolane, which are prepared from theappropriate hydroxyalkanedithiols of formula (VII).

Illustrative of the hydroxyalkanedithiols (VII) are1,Z-dimercapto-3-propanol, 1,2-dimercapto-4-butano1,1,Z-dimercapto-3-methyl-4-butano1, 1,2-dimercato-5- pentanol,1,2-dimercatpo-3,3-dimethyl-4-butano1, l,2-dimercapto-6-hexanol,l,2-dimercapto-7-heptanol, and 1,Z-dimercapto-S-octanol.

Hydroxy-substituted 1,3-oxathianes and hydroxyalkyl-substituted1,3-oxathiolanes within formula (IV) above are most convenientlyprepared by condensing an appropriate thiol-substituted alkanediol withformaldehyde (paraformaldehyde) in the presence of an acid catalyst suchas concentrated hydrochloric acid or p-toluenesulfonic acid. [method ofR. M. Roberts, et aL, J. Org. Chem, 23 983 (1958)]. Employing as thethiolsubstituted alkanediols compounds of formula:

wherein Q is an integer of from lto 7, there are obtained thecorresponding 5-hydroxyalkyl-L3- oxathiolanes such as5-(2-hydroxyethyl)1,3- oxathiolane, 5-(3-hydroxypropyl)-1,3-oxathiolane,5 l ,1-dimethyl-2-hydroxyethyl)- l ,3-oxathiolane, 5( 5-hydroxypentyl)-l,3-oxathiolane, 5-(6-hydroxyhexyl)- 1,3-oxathiolane andthe like. Compounds (VIII) are well known as illustrated byl-mercapto-2,4- butanediol, l-mercapto-2,5-propanediol, l-mercapto-3,3-dimethyl-2,4-butanediol, 1-mercapto-2.7- heptanediol,l-mercapto-2,8-octanediol and the like.

Advantageously the sulfur reactant of formula (IV) employed in preparingthe novel compounds (I) of the invention is a mixture of substantiallyequal proportions of 5-hydroxy-1,3-oxathiane and 5-hydroxymethyl-l,3-oxathiolane. Said mixture is ob tained by thecondensation of 1-mercapto-2,3- propanediol with formaldehyde accordingto the method of R. M. Roberts, et al., supra, described above.

The use of the mixture of 5-hydroxy-l,3 -oxathiane andS-hydroxymethyl-l,3-oxathiolane as the reactant (IV) in the Process A ofthe invention is a preferred embodiment resulting in a high yield ofamixture of the corresponding compounds (II) of the invention. The highproduct yield mixture of compounds (11) so obtained comprisesspecifically a mixture of the appropriate alkylN-acyl-2,3,4-tri-O-acyl-7-deoxy-7(S)-(3-acetoxymethoxy-Z-hydroxypropylthio)-60- thiolincosamide and alkylN-acy1-2,3,4-O-acy1-7- deoxy-7(S)-(2-acetoxymethoxy-3-hydroxypropylthio)-6O -thiolincosaminide. The individual components (II) of theabove described product mixture may be hydrazinolysed while inadmixture, employing conventional techniques, such as the example thehydrazinolysis prcedure set forth in US. Pat. No. 671,647, to givequantitative yields of the corresponding alkyl7(S)-(2,3-di-hydroxypropylthio)-7-deoxy-60 thiolincosaminide. The lattercompound is a useful intermediate for preparing the correspondinglincomycin hydrochloride, a useful antibacterial agent; see Iranian Pat.No. 10,395 supra.

The starting aziridino compounds (111) wherein Ac is specificallycarboxacyl are well known compounds, see for example, US. Pat. Nos.3,671,647; 3,702,322 and Iranian Pat. Nos. 10,395; 10,460.

Those starting aziridino compounds (III) wherein Ac is specifically theacyl radical of a 4-alkylsubstituted L-2-pyrrolidinecarboxylic acid,i.e., a compound of the formula:

PROCESS B The novel compounds (IX) of the invention are prepared byN-acylating an appropriate alkyl 6,7-aziridino-6-deamino-7-deoxy-a-thiolincosaminide (X) will an appropriatemixed anhydride (XI). The reaction is conveniently illustrated by theschematic formula:

wherein R R,,, Y, G and the wavy lines have the meanings previouslyascribed to them; b is an integer of from I to 3.

The process illustrated above is carried out by admixture of thereactants (X) and (XI) in substantially equimolar proportions usingconventional apparatus and techniques of mixing. Critical to the processis maintenance of the reaction mixture at a temperature of from aboutl0C. to 5C. during the course of the reaction. The required temperatureis maintained by the use of conventional methods of cooling reactionmixtures.

Advantageously, the Process B is carried out in the presence of an inertorganic solvent as previously defined. Preferred solvents areacetonitrile, nitromethane, tetrahydrofuran and dimethylformamide andmost preferably acetonitrile. Advantageously, the thitilim' cosaminidereactant (X) is solubilized in an inert organic solvent prior toadmixture with mixed anhydride reactant (XI). In this preferredembodiment, the inert solvent employed to dissolve the thiolincosaminidereactant (X) is preferably an aliphatic alcohol having a molecularweight of at least about 60. Illustrative of such aliphatic alcohols areisopropyl alcohol, n-butyl alcohol, isobutyl alcohol, tert-butylalcohol, n-hexyl alcohol, cyclohexanol and like aliphatic alcohols.

Advantageously, the above reaction is also carried out in the presenceof an acid acceptor compound such as, for example, a tertiary aminecompound. Illustrative of tertiary amines employed herein aretriethylamine, tripropylamine, tributylamine, tripentylamine,trihexylamine and the like.

The process of the above illustrated reaction for preparing compounds(IX) of the invention may be followed by conventional analytical methodssuch as, for example, thin layer chromatography which will show theappearance of the desired product compounds (IX). In general, thereaction is complete in form about 1 to about 24 hours. Upon completionof the reaction, the desired compounds (IX) are readily separated fromthe reaction mixture by conventional techniques such as by evaportion ofsolvent, solvent extaction, chromatography, counter-current distributionand like methods.

The starting thiolincosaminide reactants (X) emplayed in the abovedescribed Process B are well known compounds as is their preparation;see, for ex ample, US. Pat. Nos. 3,671 ,647 and 3,702,322. Mixedanhydride reactants of formula (XI) are for the most part well known,and are prepared by reacting an appropriate L-2-pyrrolidinecarboxylicacid or hydrochloride salt thereof of formula c OH R5 '6 (XI wherein Gand R are as defined previously, with an appropriate alkyl chloroformatesuch as, for example, ethyl chloroformate, isopropyl chloroformatae,isobutyl chloroformate and the like. The method of prepar- PROCESS CSpecific compounds (I) of the invention wherein R is the previouslydescribed thio group, and Z represents hydrogen, i.e., compounds of theformula:

wherein A, B, n X, D, Y, R and R and the wavy line to R are as definedabove; are prepared by hydrogenolysis of the corresponding compound (II)wherein Z is specifically a protective group removable byhydrogenolysis. The hydrogenolysis is carried out by known procedures,for example, by the procedure set forth in US. Pat. No. 3,380,992. Thecompounds (XIII) of the invention are useful intermediate compounds. Byknown methods, for example, as set forth in US. Pat. No. 3,366,624, theproline nitrogen in compounds (XIII) may be alkylated by reaction withan alkyl halide. Alternatively, the compounds (XIII) may be reacted withan aldehyde or ketone and the resulting adduct hydrogenated. In thismanner, the compounds (X) of the invention provide a method of preparingnovel compounds (I) of the invention having the specific formula:

(XIV) wherein R is lower alkyl, A, B, n, X, D, Y, R R and the wavy lineto R are as defined previously.

The compounds (XIV) of the invention wherein Y is specificallycarboxacyl are readily hydrolyzed by conventional techniques such as,for example, by base hydrolysis to obtain the corresponding 7-deoxy-7-hydroxyalkylthio lincomycins disclosed in copending US. application Ser.No. 199,046, filed Nov. 15, 1971, as useful antibacterial agents.

The compounds (XIV) of the invention wherein Y is specifically hydrogenare preferred compounds (I) of the invention. They are preferred becausethey possess antibacterial properties similar to, for example, the 7-deoxy-7(S)-alkylthio lincomycins disclosed in Iranian Pat. Nos. 10,395and 10,460, are useful for the same purposes as said7-deoxy-7(S)-substituted lincomycins, and are useful in the same manner.

(XIII) PROCESS D A preferred process for preparing the compounds (I) ofthe invention having the specific formula:

wherein A, B, X, R.,, R Y, D, n and the wavy line are as previouslydefined and G represents lower alkyl or a protective group removable byhydrogenolysis is carried out in a three-step procedure which comprises;

1. reacting together an appropriate aziridine of formula (X), supra. andan appropriate mixed anhydride of formula:

wherein G and R are as defined above and b is an integer of from I to 3,inclusive; at a temperature of from about 10 C. to about 5C.; (2.)warming the reaction mixture so obtained to a temperature of from about25C. to about C; and (3.) adding to the warmed reaction mixture anappropriate sulfur compound of Details for carrying out the procedure ofstep (1.) in the above described preferred Process D are those disclosedpreviously herein as Process B.

Step (2.) of Process D is carried out upon the completion of thereaction occurring in step (1.), but without separating the intermediatecompound of formula (IX) from the reaction mixture. Preferably, thewarming of the reaction mixture in step (2.) is to a temperature withinthe range of from about 60C. to about 150C. and most preferably withinthe range of from about 80C. to about 110C.

Details of the procedure for carrying out step (2.) of the Process D arethose disclosed herein as Process A, which differs only in respect tothe specific starting aziridino reactant employed.

The preferred solvents, when employed in Process A differ from thosepreferred when employed in Process B. AS expected, solvents employed inthe various steps of Process D may therefore advantageously differ. Insuch case a given solvent may be readily stripped and replaced, ifdesired, by conventional methods well known to one skilled in the art,between consecutive steps of the Process D.

PROCESS E An alternate and preferred process for the preparation ofcompounds (XIII) of the invention which were described previously ashaving the formula:

(XIII) is carried out by modifying the Process D described above,wherein in the mixed anhydride (XI), G is specifically a group removableby hydrogenolysis.

The modification of Process D comprises in step (2.) therein, warmingthe reaction mixture of step (1.) to a temperature within the range offrom about 25C. to about 50C. and prior to step (3.) carrying out anintervening step (2A.). Step (2A.) comprises subjecting the warmedreaction mixture obtained in step (2.) to catalytic hydrogenation. Theprocedure of catalytic hydrogenation is carried out by conventional andwell known methods.

In general, such methods comprise adding a catalytic proportion of ahydrogenation catalyst to the reaction mixture and agitating thereaction mixture under a hydrogen gas atmosphere of from I to about 50atmospheres of pressure. The technique is well known; see for exampleU.S. Pat. No. 3,380,992, Example 2, part (C) for details of such ahydrogenation. Upon completion of the hydrogenation step, which isgenerally complete in about 3-24 hours, as evidenced by cessation ofhydrogen consumption, step (3.) of Process D is commenced. Preferablythe hydrogenated mixture is first filtered to remove catalyst residuebefore proceeding to said step (3.)

The above described Processes D and E are particularly advantageousbecause they provide a method for the continuous production of thedesired compounds (XIII) and (XV) from the basic aziridino (X) withouthaving to isolate the appropriate intermediates which have the formula(IX). This is an important advantage for a number of reasons, forexample, certain of the intermediates formed, particularly the alkyl N-(l-alkyl-4-propyl-L-prolyl)-6,7-aziridino-6-deamino-7-deoxy-ozthiolincosaminidesand the alkyl N-( L-2- pyrrolidinecarboxacyl)-6-7-aziridino-6-deamino-7-deoxy-a-thiolincosaminides are difficult to separate as pure materialsin high yields. The continuous methods of Processes D and E thereforeprovide in these instances the most practical processes from acommercial viewpoint.

The following preparations and examples describe the manner and processof making and using the invention and set forth the best modecontemplated by the inventor of carrying out the invention but are notto be construed as limiting.

Preparationl. 5-l-Iydroxy-l ,3-oxathiane and5-hydroxymethyl-1,3-oxathiolane A mixture of 200 grams (1 molarequivalent) of 2,3-dihydroxypropanethiol (a-thioglycerol), 55.6 grams (1molar equivalent) of paraformaldehyde, 1.0 gram of p-toluenesulfphonicacid, and 750 ml. of benzene is heated in an oil-bath at C in aDean-Stark water-separator apparatus for 12 hours while beingcontinually stirred. At the end of this period, benzene is removed fromthe reaction mixture by distillation at atmospheric pressure and thenunder 7 mm. of mercury. The residue is subjected to distillation underhighvacuum, and gives as a residue a colorless liquid, b.p. 66-67C. at0.5 mm. of mercury, which is a mixture of 5-hydroxy-1,3-oxathiane and5-hydroxy-methyl-l,3- oxathiolane in about equal proportions. Structureof the mixture components is confirmed by vapor phase chromatography andmass spectral analysis. This product mixture was demonstrated to be freeof thio starting material by the method of Feigl, Spot Tests in OrganicAnalysis, 7th English Ed., (1966), Elsevier Publ. Co., N.Y., N.Y., pps.219- 220.

Anal. Calcd. for: C l-I O S (percent): C, 39.98; H,

6.71; S, 26.69. Found (percent): C, 39,64; H, 6.83; S, 27.07

EXAMPLE 1 Methyl N-[ l-carbobenzoxy-trans-4-propyl-L-pro|yl]- 6(R),7(R)-aziridino-6-deamino-7-deoxy-athiolincosaminide.

To a solution of 2.91 grams (1 molar equivalent) of1-carbobenzoxy-trans-4-propyl-L-proline (prepared by N-carboxylation oftrans-4-propyl-L-pro1ine, (prepared according to the method of copendingU.S. application Ser. No. 220,389, filed Jan. 24, 1972) in 100 ml. ofanhydrous acetonitrile, there is added 1.11 grams of triethylamine (1.53ml.; 1.1 molar equivalents) with stirring. The stirred solution iscooled to 31 C. in an icemethanol bath. To the resulting mixture 1.36grams (1.30 ml.; 1 molar equivalent) if isobutyl chloroformate is addedand the mixture stirred for 20 minutes while maintaining the temperatureat circa -5C. A precipitate of triethylammonium chloride is formed.

A suspension of 2.35 grams (1 molar equivalent) of methyl6(R),7(R)-aziridino-6-deamino-7-deoxy-athiolincosaminide in 50 ml. ofisopropyl alcohol is added to the above mixture, and the mixture allowedto stir without replenishing the coolant. THe aziridine dissolves duringthe course of circa minutes. The solvent is removed on a rotaryevaporator at 40C. under 7 mm. of mercury and the residue is dissolvedin methanol and the solution made basic (circa pH 10) by addition of 6Nsodium hydroxide. After about 1 hour, solvent is removed as above andthe residue is partitioned between methylene chloride and water. Themethylene chloride extract is washed with water and dried over anhydroussodium sulfate. Removal of the solvent gives an amorphous solid (5.08grams, 100 percent of theory) of methyl N-[ 1-carbobenzoxytrans-4-propyl-Lprolyl]-6(R), 7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide. Structure of the product is confirmed by theinfra-red spectrum which shows the 1,700 cm absorption of anacylaziridine.

EXAMPLE 2 Methyl N-acetyl-2,3 ,4-tri-O-acetyl-7-deoxy-7(S)-( 2-acctoxymethylthio)-ethylthio-a-thiolincosaminide.

An appropriate reaction vessel is charged with 5.0 grams 1 molarequivalent) of methyl 2,3,4-tri-O- acctyl6(R),7(R)-acetylaziridino-6-deamino-7deoxya-thiolincosaminide (preparedaccording to the method of Example '19, Part l9-A, US. Pat. No.3,671,647), 50 grams of 1,3-dithiolane and 5.25 grams (5.0 ml.; 7 molarequivalents) of glacial acetic acid. The resulting mixture is heated forabout twenty hours in an oil bath maintained at a temperature of about100C. At the end of this period, the reaction mixture is distilled at atemperature of 100C. and under pressure of 7 mm. of mercury. The solidresidue is partitioned between water and methylene chloride. THe organiclayer is separated and washed with saturated aqueous sodium bicarbonateand then with water. The washed solution is dried over anhydrous sodiumsulfate. The dried material is counter-current distributed in the systemethanol-water-ethyl acetate-cyclohexane l :1 :1:3,v/v/v/v) to obtainmethyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxymethylthio)ethylthioa-thiolincosaminide ata K value of 0.98. Recrystallized from ethyl acetateSkellysolve B, thereis obtained 5.83 grams (83 percent of theory) ofthe product in the formof colorless needles, M.P. 164C. 165C, [01],, +l67 (C, 0.97, CHCl"Essentially nhexane, B. P. 60C.-68C., Skellysolve Oil Co., Inc.

Anal. Calcd. for: C H NO S (percent): C, 46.38;

H, 6.19; N, 2.46; S, 16.89; M.W., 569 Found (percent): C, 46.07; H,6.18; N, 2.29; S,

16.85; M.W. (Mass Spec., M") 569.

Similarly, following the above procedure, but replacing the1,3-dithiolane as used therein with equal molar proportions of thefollowing sulfur compounds of formula (1V); 1,3-oxathiane,5-hydroxy-l,3-dithiane, 4- hydroxymethyl-l,3-dithiolane and4(6hydroxyhexy1)- 1,3-dithio1ane, respectively, there is obtained methyl18 N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(3-acetoxymethoxy)propylthio-a-thiolincosaminide, methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(3-acetoxymethylthio-Z-hydroxypropylthio)-athiolincosaminide, a mixture ofmethyl Nacetyl-2,3.4- triO-acctyl-7-deoxy-7(S)-(2-acetoxymethylthio-3-hydroxypropylthio)-a-thiolincosaminide and methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy'7(S)-(3-acetoxymethylthio-1-hydr0Xypropyl-2-thio)-athiolincosaminide and amixture of methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxymethylthio-8-hydroxyoctylthio)-a-thiolincosaminide and methylN-acetyl-Z,3,4-tri-O-acetyl-7-deoxy-7(S)-(1-acetoxymethylthio-8-hydroxyoctyl-2-thi0)-athiolincosaminide,respectively. The above isomeric mixtures are readily separated intotheir isomer component parts by conventional methods, such as bychromatographic techniques, when separation is desired.

EXAMPLE 3 Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S 3-acetoxymethylthio)-propylthio-a-thiolincosaminide.

An appropriate reaction vessel is charged with 5.0 grams (1 molarequivalent) of methyl 2,3,4-tri-O- acetyl-6(R),7(R)-acetylaziridino-6-deamino-7-deoxy- (it-thiolincosaminide (supra),and 50 grams of 1,3- dithiane. The mixture is heated until molten. Tothe molten mixture there is added 5.25 grams (5.0 ml., 7 molarequivalents) of glacial acetic acid and the reaction mixture is thenstirred while warmed in an oil bath maintained at a temperature of 100C.for about 20 hours. At the end of this period, the reaction mixture isallowed to cool, methanol ml.) is added and the crystalline 1,3-dithianewhich separates (24.5 gm.) is removed by filtration. The filtrate isevaporated to dryness on a rotary evaporator at 40C. (7 mm. of mercurypressure). The dry residue is chromatographed on silica gel (3 Kg.column, 10.5 cm. X 72 cm.) in ethyl acetate Skelly-solve-B (supra) 1:1,v/v) to remove unreacted 1,3-dithiane residues (total eluate 9.5liters). The eluant is then changed to ethyl acetate to strip thecolumn. An aliquot of the final eluate shows, by thinlayerchromatography, a major material with traces of contaminants of lowerR".

Counter-current distribution of the final eluate in ethanol-water-ethylacetate-cyclohexane 1:1 l :3, v/v/v/v) gives methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(S)-(3-acetoxymethylthio)propylthio-athiolincosaminide at a Kvalue of 1.29. Recrystallization from ethyl acetate-Skellysolve-B (1:1,v/v) gives 4.97 grams (69 percent of theory) of the product in the formof colorless prisms, M.P. 131.5C. 132.5C;

[01],, =+164 (C. 0.94, CHCl Anal. Calcd. for: C H NO S (percent): C,47.32;

H, 6.39; N, 2.40; S, 16.48; M.W. 583 Found (percent): C, 47.49; H, 6.40;N, 2.04; S,

16.20; M.W. (Mass Spec., M*) 583 EXAMPLE 4 MethylN-acetyl-2,3,4-tri-O-acetyl-7 deoxy-7(S2-acetoxymethoxy)-ethy|-thio-alincosaminide.

An appropriate vessel is charged with 5.0 grams (1 molar equivalent) ofmethyl 2,3,4-tri-O-acetyl-6(R),7(R)-acetylaziridino-6-deamino-7-deoxy-athiolincosaminide (supra), 50grams of 1,3- oxathiolane and 5.25 grams (5.0 ml.; 7 molar equivariod,the reaction mixture is distilled at a temperature of 100C. and under apressure of 7 mm. of mercury. The solid residue is partitioned betweenwater and methylene chloride. The organic layer is separated and washedwith saturated aqueous sodium bicarbonate and then with water.- Thewashed solution is.dried over anhydrous sodium sulfate. The residueobtained from the dried solution by removal of solvent is countercurrentdistributed in the system ethanol-water-ethyl acetate-cyclohexane 1 l 1:2, v/v/v/v) to obtain methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxymethoxy)ethylthio-a-thiolincosaminide at a K value of 0.70.Recrystallized from ethylacetate- Skellysolve-B (1:1, v/v), 5.7 grams(83percent of theory) of the product is obtained in the form of colorlessneedles, M.P. 148C. 149C, [db +158 (C, 1.01; CHCl Anal. Calcd. for: Cl-l NO S (percent): C, 47.72;

H, 6.37; N, 2.53; S, 11,58; M.W. 553 Found (percent): C, 47.91; H, 6.50;N, 2.40; S,

11.37; M.W. (Mass Spec, M) 553 EXAMPLE MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(3-acctoxymethoxy-2-hydroxypropyl)thio-athiolincosaminide and methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-( 2-acetoxymethoxy-3-hydroxypropyl)thio-athiolincosaminide To 50 grams ofthe mixture of 5-hydroxy-1,3- oxathiane and5-hydroxymethyl-l,3-oxathiolane obtained in Preparation 1., supra.,there is added with stirring 10.0 grams of methyl2,3,4-tri-O-acetyl-6(R), 7(R-)-acetylaziridino-6-deamino-7-deoxy-athiolincosaminide (supra), and 5.25grams (5.0 ml., 3.5 molar equivalents) of glacial acetic acid. Theresulting solution is heated for circa 20 hours in an oil-bathmaintained at a temperature of circa 100C. Volatile material is thenremoved by distillation at a temperature of 100C. under a pressure of 1mm. of mercury. The solid residue is partitioned between water andmethylene chloride, and the washed methylene chloride extract dried overanhydrous sodium sulfate. Removal of the solvent gives a solid residuewhich is subjected to counter-current distribution in the systemethanol-water-ethyl acetate-cyclohexane (1:1:1:O.5, v/v/v/v) to obtain3.75 grams (52 percent of theory) of a mixture of methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(3-acetoxymethoxy)2-hydroxy-propy1thio- (Jr-thiolincosaminideand methyl N-acety1-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxymethoxy-3-hydroxypropyl)-thio-a-thiolincosaminide at a K value of 1.14. While thematerials are present as a welldefined peak, thin-layer chromatographyreveals the presence of the two materials in about equal proportions.

EXAMPLE 6 Methyl N-( 1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-dexoy- 7(S 2-acetoxymethoxy)-ethylthio-athiolincosaminide,

To 5.0 grams of methyl N-( l-carbobenzoxy-trans-4- 20propyl-L-prolyl)-6-7-aziridino-6-deamino-7-deoxy-athiolincosaminide(prepared according to Example 1., supra.) there is admixed 50 grams of1,3-oxathiolane and 4.2 grams (4.0 ml.; 7 molar equivalents) of glacialacetic acid.

The resulting solution is heated in an oil-bath at C. with magneticstirring for 20 hours. At the end of this time, thin-layerchromatography (silica gel; methanol-chloroform, 1:7 v/v) of an aliquotof the reaction mixture shows the absence of the startingthiolincosaminide material (R, 0.51) and the generation of a new zone ofproduct (R, 0.57). The reaction mixture obtained is chromatographed onsilica (1,200 grams, column dimensions 5.8 X 93 cm.). Elution isconducted with the solvent system ethyl acetate-Skellysolve B, 3:1 v/vuntil 1,500 mls. of eluate has been collected, and then the solventsystem is altered to ethyl acetate- Skellysolve B-methanol (3:l:0.2,v/v/v) collecting 50 ml. fractions throughout.

Combination of fractions, Nos. 261-340, inclusive, and removal of thesolvent under the standard conditions gives 4.10 grams (63 percent oftheory) of methyl N-1-carbobenzoxy-trans-4-propy1-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-athiolincosaminide in the form of asyrup. Structure of the product is confirmed by nuclear magneticresonance analysis which shows the characteristic absorption spectra ofthe substituted side chain, and by infrared analysis which shows acharacteristic absorption at 1,740 cm" and 1,660 cm' EXAMPLE 7 MethylN-( trans-4-propyl-L-prolyl )-7-deoxy-7(S )-(2- acetoxymethoxy)ethylthio-a-thiolincosaminide An appropriate vessel is charged with2.87 grams of methyl N-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)ethylthio-ozthiolincosaminide (Example 6,supra) and 1.5 grams of 10 percent palladium on charcoal. The mixture ishydrogenated at an initial pressure of 50 p.s.i. of hydrogen at roomtemperaturefor 24 hours. At the end of this period, thin-layerchromatography (silica gel, ethyl acetate-Skellysolve B-methanol,31110.2 v/v/v) of an aliquot of the reaction mixture shows the absenceof the starting carbobenzoxy compound (R, 0.35) and the presence of anew zone at the origin (i.e., R,0.0). Thinlayer chromatography of thereaction solution on silica gel in the solvent system(methanol-chloroform, 1:5 v/v) shows methylN-(trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)ethylthio-athiolincosaminide at R, 0.42.

The following example illustrates the use of the compounds (ll) of theinvention as intermediates in the preparation of compounds having knownvalue and usefulness.

EXAMPLE 8 To 3.75 grams of the mixture of methyl N-acetyl-2,3,4-tri-O-acetyl-7deoxy-7(S)-( 2-acetoxymethoxy-3hydroxypropyl)thio-a-thiolincosaminidc and methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S 3-acetoxymethoxy-2-hydroxypropyl)-thio-athiolincosaminide obtained inExample 5, supra.) there is added 100 grams of hydrazine hydrate. Theresulting mixture is heated under gentle reflux in an oil bathmaintained at C. for about 22 hours. At the end of this period, excesshydrazine hydrate is distilled under vacuum and the residue crystallizedfrom 10 ml. of methanol-acetonitrile mixture to obtain 2.21 grams (100percent of theory; 26 percent of theory based on starting methylN-acetyl-2,3,4-tri-O-acetyl-6(R), 7(R)- aziridino-6-deamino-7-deoxy-oz-thiolincosaminide) ofmethyl-7-deoxy-7(S)-(2,3-dihydroxypropylthio)-athiolincosaminide, in theform of colorless prisms, M.P. 158C. to 159C.

EXAMPLE 9 This Example is not an example of the invention, but followsthe procedure of Example 25 in Iranian Pat. 10,395 and by comparison toExamples and 8 herein, shows, the improved product yield obtained by theprocess of this invention.

A mixture of 5.0 grams (1 molar equivalent) methylN-acetyl-2,3,4-tri-O'acetyl-6(R), 7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide, 50 cos. of 2,3-dihydroxypropylmethyl sulfide, and 5.25 grams (7 molar equivalents) glacial acetic acidis heated in a Pyrex sealed tube for 20 hours in a steam-bath. Volatilematerials are removed from the reaction mixture by distillation at100C., the residue is dissolved in methylene chloride and stirred withan excess of saturated aqueous sodium bicarbonate. Washing of theorganic layer with water, drying over anhydrous sodium sulfate, andremoval of the solvent on a rotary evaporator at 40/7 mm. gives a solid.

Counter-current distribution of this solid in the system 1 ethanolzlwater:1.5 ethyl acetate:0.5 cyclohexane (v/v/v/v) gives 1.02 grams (16.2percent of theory) of methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2,3-dihydroxypropyl)thio-a-thiolincosaminide at a K value of 0.91, ascolorless platelets from ethyl acetate; mp. 255C. 257C.

[01],, +l64 (C, .67, chloroform) To 900 mg. of the acylated product soobtained, there is added 100 ml. of hydrazine hydrate. The mixture isstirred and heated under gentle reflux in an oil bath at 160C. for 22hours. Removal of the volatile material from the colorless solution bydistillation from the oil bath at 1 l0C./7 mm. gives 600 mg. (circa 100percent of theory) of methyl 7-deoxy-7(S)-(2,3-dihydroxypropylthio)-a-thiolincosaminide, M.P. 158C. to 159C. (overallyield based on starting methyl N-acetyl-2,3,4-tri-O-acetyl-6(R),7(R)-aziridin0-6-deamino-7-deoxy-0t-thiolincosaminide is circa 16.6 percentof theory).

EXAMPLE Methyl N-( l-methyl-trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide.

l-Methyl-trans-4-propyl-L-proline hydrochloride (4.41 gm., 1 molarequivalent) is suspended in acetonitrile (100 ccs.) with stirring atroom temperature, and triethylamine (4.3 gm., 5.9 ml., 2 molarequivalents) is added to the suspension. The resulting solution is thencooled to -5C. in an ice-methanol bath. A precipitate oftriethylammonium chloride appears. lsobutyl chloroformate (2.9 gm., 2.79ml., 1 molar equivalent) is added to the last mixture at such a ratethat the temperature of the reaction mixture remains between 5C. and 0C.and the resultant mixture is stirred at a temperature of -5 for anadditional 5 minutes. A slurry of 5.0 gm. (1 molar equivalent) of methyl6(R),7(R)- aziridino-(i-deaminc-7-deoxy-a-thiolincosaminide in isopropylalcohol 120 ccs.) is added, and the reaction mixture stirred and allowedto warm to room temperature. After 2 hours, thin-layer chromatographyshows the absence of aziridine starting reactant (R, 0.09) and theappearance of a new zone of R, 0.3 1. Removal of volatile solvents on arotary evaporator at 40 and 7 mm. of mercury give a residual syrupcontaining methyl N-[ l-methyl-trans-4-propyl-L-prolyl]-6(R),7(R)-a2iridino-6-deamino-7-deoxy-a-thiolincosaminide.

The latter compound is separated from the syrup residue, when separationis desired, by first dissolving said residue inmethylene chloride. Theresulting solution is made mildly alkaline, preferably to a pH of circa8.3 by the addition of aqueous sodium bicarbonate. The resulting mixtureis shaken and the organic phase separated. The organic phase, afterseparation, is washed with water, dried and evaporated to give purifiedmethyl N-( l-methyl-trans4-propyl-L-prolyl6(R),7(R)-aziridino-6-deamino-7-deoxy-athiolincosaminide, which isuseful as an intermediate for preparing the corresponding lincomycin.

Similarly, following the above procedure but replacing thel-methyl-trans-4-propyl-L-proline hydrochloride as used therein with anequal molar proportion of l-n-hexyl-4-propyl-L-proline hydrochloridethere is obtained methyl N-(l-n-hexyl-4-propyl-Lprolyl)-6(R),-7(R)-aziridino-6-deamino-7-deoxy-ozthiolincosaminide.

EXAMPLE 1 1 Methyl N-( 1-methyl-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(Z-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

Without separating the methyl N-(1-methyl-trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide from the residual syrup last described inExample 10., supra, said residual syrup is admixed with 65 grams (34molar equivalents) of 1,3- oxathiolane and the mixture is stirred andheated in an oil-bath at C. until the reaction mixture is a solution.Glacial acetic acid (8.9 gm., 8.5 ml., 7 molar equivalents) is thenadded to the solution and heating is maintained for 18 hours. At the endof this period, volatile material is removed from the reaction solutionby distillation from the oil-bath at 100 under diminished pressure togive a syrupy residue, showing a major product by thin-layerchromatography (silica gel, methanol-chloroform, 1:7 v/v), R, 0.49,which is methyl N-( l-methyl-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-athiolincosaminide. The lattercompound may be separated from the residue in pure form, when desired,by conventional methods for example by chromatography andcounter-current distribution.

Similarly, following the above procedure but replacing the syrup residuecontaining methyl N-(l-methyltrans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide as used therein with methyl N-(1-n-hexyl-4-propyl-L-prolyl6(R),7(R)-aziridinol6-deamino-7-deoxy-athiolincosaminide, there isobtained methyl N-( l-nhexyl-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

EXAMPLE 12 This example is not an example of the invention butillustrates the hydrolysis of compounds (IX) of the invention to obtainuseful antibacterial agents.

Without separating the methyl N-( l-methyl-trans-4-propyl-L-prolyl-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide from the syrupy residue last described inExample 11., supra., said syrup residue is dissolved in methanol (50ml.), adjusted to a pH of about by the addition of aqueous sodiumhydroxide (1N), and allowed to stand at room temperature for 1 1; hours.Methanol is then removed from the alkaline solution on a rotaryevaporator at 40C. under 7 mm. of mercury, and the residual aqueouslayer is extracted with chloroform. The extract is dried over anhydroussodium sulfate. Removal of solvents on a rotary evaporator at 40 under 7mm. of mercury gives a colorless syrup, (7.69 gm. Chromatography onsilica gel (1,200 gm., column dimensions 5.8 X 91 cm.) is conducted withmethanol-methylene chloride, (1:12 v/v) and 50 cc. fractions arecollected. Fractions ll4-214, inclusive, are pooled and solvent strippedfrom the combined fractions to give a syrup residue which is 7-deoxy-7(S)-(2-hydroxyethylthio) lincomycin, a useful antibacterialagent; see Iranian Pat. No. 10,407.

EXAMPLE l3 Methyl N-[ trans-4-propyl-L-prolyl ]-6( R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide.

To a solution of 5.08 grams (10 moles) of methyl N-l-carbobcnzoxy-trans-4-propyl-L-prolyl]-6(R),7(R)-aziri'dino-b-deamino-7-deoxy-a-thiolincosaminide (Example 1, supra.) in200 ml. of methanol, there is added 0.50 grams of 10% palladium oncarbon. The mixture is charged to a Parr low pressure hydrogenationvessel and agitated for about 24 hours under a hydrogen gas atmosphereat a pressure of about 50 psi (gauge); at the end of this period, thereaction mixture is filtered and the solvent removed by evaporation. Theresidue is a crude mixture containing methyl N-[trans-4-propyl-L-prolyl]-6(R),7(R)-aziridino-6-deamino-7-deoxy-athiolincosaminide. Whendesired, the methyl N-[trans-4-propyl-L-prolyl]-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thioloicosaminide may be separated from the crude mixture byconventional methods of separation. For example, the mixture may bedissolved in methanol, filtered to remove solid residues, and thefiltrate made mildly alkaline, preferably to a pH of circa 8.3 by theadditio'n of base, preferably sodium bicarbonate. The alkaline solutionis then evaporated and the residue partitioned between methylenechloride and water. The methylene chloride extract upon washing withwater, drying and evaporation of solvent yields methyl N-[trans-4-propyl-L-propyl]-6(R),7(R)-aziridino-6-deamino'7-deoxy-a-thiolincosaminide in purified form.

EXAMPLE l4 Methyl N-(trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

The crude mixture containing methyl N-(trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide as obtained in Example 13.,

supra., is admixedwith 27.0 grams (300 mmoles) of 1,3-oxathiolane andheated in an oil bath at 100C. until the mixture is a solution. To thesolution there is added 4.2 grams mmoles) of glacial acetic acid and theresulting mixture is stirred for about 18 hours while maintaining thetemperature of the reaction mixture at about C. At the end of thisperiod, solvent is stripped from the reaction mixture to obtain aproduct residue which is crude methyl N-(trans-4propyl-L-propyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthiotit-thiolincosaminide.

The product is readily purified by conventional chromatographic methodsto give purified methyl N-(trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

Compounds (1) of the invention having the specific formula:

wherein L is selected from hydrogen and lower alkyl, R, and R are eachlower alkyl and Y is selected from hydrogen and carboxacyl areparticularly valuable intermediates for the synthesis of a wide varietyof lincomycin analogs. For example, the compounds (XVl) of the inventionmay be substituted for alkyl N-acyl-6(R),-7(R)-aziridino-6-deamino-7-deoxy-o1- thiolincosaminides in theprocesses of U.S. Pat. Nos. 3,544,551; 3,671,647; 3,702,322; lranianPat. Nos. 10,395; 10,407 and 10,460, supra. Such a substitution yieldsas a product of said processes, the respective lincomycin analogs, thusobviating the necessity of removing the N-carboxacyl group and replacingit with the N-L-Z-pyrrolidinecarboxyacyl group when the lincomycinderivative is the ultrimate product desired. This advantage is ofparticular importance in those instances wherein removal of anN-carboxacyl blocking group may occur concurrently with the undesiredremoval of an acyl group from another portion of the thiolincosaminidemolecule. For example, when in a compound (ll) of the invention whereinAc, and D are both carboxacyl groups, it may be desirable to replace theAc carboxacyl group with an L-2- pyrrolidinecarboxylic group whileretaining the carboxacyl group D. This may be accomplished by employingthe appropriate compound (XVl) as the starting reactant (III) in ProcessA, supra.

1 claim: 1. A compound of the formula:

wherein R when taken independently represents hy-' drogen; R when takeneindependently represents the monovalent moiety wherein Ac is selectedfrom carboxyacyl of from 2 to 18 carbon atoms, inclusive, and an acylradical of formula:

wherein Z is selected from hydrogen, lower alkyl and an amino protectinggroup removable by hydrogenolysis; R is lower alkyl; R and R when takentogether form the divalent group of the formula:

wherein Z and R are as defined above; R is hydrogen when R and R aretaken together and when R and R are taken independently, R is amonovalent thio group in the 7(S)-position, having the formula:

wherein A is selected from hydrogen and hydroxy, B is selected fromhydrogen and monohydroxyloweralkyl, n is the integer when B ismonohydroxyloweralkyl and an integer of from 0 to I when E is hydrogen,X is selected from oxygen and sulfur, D is an acyl radical of a lowerhydrocarbon carboxylic acid; R represents lower alkyl; and Y is selectedfrom carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogen.

2. A compound of the formula:

wherein A is selected from hydrogen and hydroxyl; B

wherein Z is selected from hydrogen, lower alkyl and an amino protectinggroup removable by hydrogenolysis; and R is lower alkyl; R representslower alkyl; and Y is selected from carboxacyl of from 2 to 18 carbonatoms, inclusive, and hydrogen.

3. A process for preparing compounds of the formula:

wherein A is selected from hydrogen and hydroxy; B is selected fromhydrogen and monohydroxyloweralkyl; n is the integer 0 when B ismonohydroxyloweralkyl and n is an integer of from 0 to l, inclusive,when B is hydrogen; X is selected from oxygen and sulfur; D is the acylradical of a lower hydrocarbon carboxylic acid; Ac is selected fromcarboxyacyl of from 2 to 18 carbon atoms, inclusive, and an acyl radicalof formula:

C R u 0 wherein AC R and Y are as defined above;

2. an anhydrous lower hydrocarbon carboxylic acid;

and 3. a corresponding sulfur compound of formula:

W x CH Wei B A wherein X, A, B, and n are as defined above. 4. Acompound of the formulal:

wherein A is selected from hydrogen and hydroxyl; B is selected fromhydrogen and monohydroxyloweralkyl; n is the integer 0 when B ismonohydroxyloweralkyl and n is an integer of from 0 to l, inclusive,when B is hydrogen; X is selected from oxygen and sulfur; D is the acylradical of a lower hydrocarbon carboxylic acid; Y is selected fromcarboxacyl of from 2 to l8 carbon atoms, inclusive, and hydrogen; R andR are each lower alkyl.

5. A compound according to claim 4 which is methylN-(trans-4-propyl-L-prolyl)-7-de0xy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

6. A compound of the formula:

. wherein A is selected from hydrogen and hydroxyl; B

is selected from hydrogen and monohydroxyloweralkyl; n is the integer 0when B is monohydroxyloweralkyl and n is an integer of from O to l,inclusive, when B is hydrogen; X is selected from oxygen and sulfur; Yis selected from carboxacyl of from 2 to 18 carbon atoms, inclusive, andhydrogen, R R and R are each lower alkyl.

7. A compound according to claim 6 wherein Y is hydrogen.

8. A compound according to claim 6 which is methyl N-(l-methyl-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-a-thiolincosaminide.

9. A compound of the formula:

wherein G is selected from lower alkyl and an amino protecting groupremovable by hyrogenolysis; R and R each represent lower alkyl and Y isselected from carboxacyl of from 2 to 18 carbon atoms, inclusive, andhydrogen.

10. The compound of claim 9 wherein Y is hydrogen.

11. A compound according to claim 9 which is methyl N-(l-carbobenzoxy-trans-4-propyl-L-prolyl)- 6,7aziridino6-deamino-7-deoxy-a-thiolincosaminide.

wherein G is selected from lower alkyl and an amino protecting groupremovable by hydrogenolysis; R and R are each lower alkyl, Y is selectedfrom carboxacyl of from 2 to 18 carbon atoms, inclusive, and hydrogenwhich comprises N-acylating a thiolincosaminide compound of formula:

CH c H wherein Y and R are as defined above; with a mixed anhydride offormula:

wherein G and R are as defined above; b is an integer of from 1 to 3, ata temperature of from about l0C. to 5C.

13. A process according to claim 12 wherein said thiolincosaminide issolubilized in an aliphatic alcohol having a molecular weight of atleast about 60 prior to N-acylation.

14. A process according to claim 12 wherein said thiolincosaminidecompound reactant is methyl 6(R), 7(-R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide, said mixed anhydridein N-[ l-carbobenzoxy-trans-4- propyl-L-prolyl]-butylcarbonic anhydrideand the product of the process is methyl N-[l-carbobenzoxytrans-4-propyl-L-proply]-6(R),7(R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide.

15. A process for preparing compounds of the formula:

wherein G is selected from lower alkyl and a amino protecting groupremovable by hydrogenolysis; R and r are each lower alkyl; Y is selectedfrom hydrogen and carboxacyl of from 2 to 18 carbon atoms, inclusive; Ais selected from hydrogen and hydroxyl; B is selected from hydrogen andmonohydroxyloweralkyl; n is the integer 0 when B ismonohydroxyloweralkyl and n is an integer of from 0 to l, inclusive,when B is hydrogen; X is selected from oxygen and sulfur; and D is theacyl radical of a lower hydrocarbon carboxylic acid, which comprises:

i. reacting together an appropriate aziridine of formula:

wherein Y and R are as defined above; and an apinclusive, and hydrogen;A is selected from hydrogen propriate mixed anhydride of formula: andhydroxyl; B is selected from hydrogen and monohydroxyloweralkyl; n isthe integer when B is monohydroxyloweralkyl and n is an integer of from0 to l, inclusive, when B is hydrogen; X is selected from oxygen andsulfur; and D is the acyl radical of a lower hydrocarbon carboxylicacid, which comprises:

1. reacting together an appropriate aziridine compound of formula:

R v CH3 wherein G and R are as previously defined and b is an integer offrom l to 3, inclusive; at a temperature of from about l()C. to about5C.;

2. warming the reaction mixture so obtained to a temperature of fromabout C. to about 180C; and

3. adding to said warmed reaction mixture (I) an appropriate sulfurcompound of the formula:

wherein Y and r are as defined above; and an appro- 25 priate mixedanhydride of formula: J H-- S l 2 N X CH I n R c- 0- c- 0--(CH CH B A nb wherein X and n are as defined above and wherein R is as definedabove, J is an amino protectan anhydrous lOWCI' hydrocarbon carboxylicacid. ing group removable by hydrogenolysis and b is an 16. The processof claim 15 he e m hyl integer of from 1 to 3, inclusive; at atemperature R)-aziridino-6-deamino-7-deoxy-a-thiolincosaminide f f about-10C, to b t 5C is reacted with N-[ l-carbobenzoxy-tran -4-pr py -L- 2.warming the reaction mixture so obtained to a prolyl]-butylcarbonicanhydride in step (1.) and the product thereof is added to1,3-oxathiolane and acetic temperature of from about 25C. to about 50C.;

3. subjecting said warmed reaction mixture to cataacid in step (3.)whereby there is obtained) methyl N- l tic h dro enation; d(l-carbobenzoxy-trans-4-propyl-L-prolyl)-7-de0Xy- 4. adding to saidhydrogenated mixture (I) an appro- 7(S)-(2-a t xym t y)- y priate sulfurcompound of the formula: thiolincosaminide. 17. A process for preparingcompounds of the forf 2 mula: X H 2 I i n B A CH H l A l H S CH -(C)C-X-CH -0-D i l. L R E N C H wherein A, B, X and n are as defined aboveand (ll) wherein R and R each represent lower alkyl; Y is sean anhydrouslower hydrocarbon carboxylic acid. lected from carboxacyl of from 2 tol8 carbon atoms, 18. A compound of the formula:

1. A COMPOUND OF THE FORMULA:
 1. A compound of the formula:
 1. thecorresponding alkyl N-acyl-6,7-aziridino-6-deamino-7-deoxy- Alpha-thiolincosaminide of formula:
 1. reacting together an appropriateaziridine of formula:
 1. reacting together an appropriate aziridinecompound of formula:
 2. warming the reaction mixture so obtained to atemperature of from about 25*C. to about 180*C.; and
 2. an anhydrouslower hydrocarbon carboxylic acid; and
 2. A compound of the formula: 2.warming the reaction mixture so obtained to a temperature of from about25*C. to about 50*C.;
 3. subjecting said warmed reaction mixture tocatalytic hydrogenation; and
 3. A process for preparing compounds of theformula:
 3. a corresponding sulfur compound of formula:
 3. adding tosaid warmed reaction mixture (I) an appropriate sulfur compound of theformula:
 4. A compound of the formula:
 4. adding to said hydrogenatedmixture (I) an appropriate sulfur compound of the formula:
 5. A compoundaccording to claim 4 which is methylN-(trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio-Alpha -thiolincosaminide.
 6. A compound of the formula:
 7. A compoundaccording to claim 6 wherein Y is hydrogen.
 8. A compound according toclaim 6 which is methylN-(1-methyl-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio- Alpha -thiolincosaminide.
 9. A compound of the formula: 10.The compound of claim 9 wherein Y is hydrogen.
 11. A compound accordingto claim 9 which is methylN-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-6,7-aziridino-6-deamino-7-deoxy-Alpha -thiolincosaminide.
 12. A process for preparing compounds of theformula:
 13. A process according to claim 12 wherein saidthiolincosaminide is solubilized in an aliphatic alcohol having amolecular weight of at least about 60 prior to N-acylation.
 14. Aprocess according to claim 12 wherein said thiolincosaminide compoundreactant is methyl 6(R), 7(R)-aziridino-6-deamino-7-deoxy- Alpha-thiolincosaminide, said mixed anhyDride inN-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-butylcarbonic anhydride andthe product of the process is methylN-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy- Alpha -thiolincosaminide.
 15. A process for preparing compoundsof the formula:
 16. The process of claim 15 wherein methyl 6(R),7(R)-aziridino-6-deamino-7-deoxy- Alpha -thiolincosaminide is reactedwith N-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-butylcarbonic anhydridein step (1.) and the product thereof is added to 1,3-oxathiolane andacetic acid in step (3.) whereby there is obtained) methylN-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio- Alpha -thiolincosaminide.
 17. A process for preparingcompounds of the formula:
 18. A compound of the formula:
 19. A compoundaccording to claim 18 which is methylN-(trans-4-propyl-L-prolyl)-6(R),7(R)-aziridino-6-deamino-7-deoxy- Alpha-thiolincosaminide.
 20. a compound according to claim 2 which is methylN-(1-carbobenzoxy-trans-4-propyl-L-prolyl)-7-deoxy-7(S)-(2-acetoxymethoxy)-ethylthio- Alpha -thiolincosaminide.